EP0366156A1 - Composition for the treatment of diseases of the veins and the anal region - Google Patents

Abstract

The invention describes an agent containing at least 100 mg of vitamin E for the treatment of diseases of the veins and of the anal region.

Description

The present invention relates to a new use of vitamin E.

Vitamin E is known as an antioxidant and protective vitamin for phosphorus lipids in the cell membrane. It maintains the permeability and stability of the cell membrane; Lucy, Ann. N.Y. Academy of Science 203 1972, p. 4. It is also known that vitamin E has a membrane sealing effect; F. Mittelbach and G. Bodechtel, Munich Medical Weekly Bulletin 110 (1968) 36, pp. 1988-1993. With erythrocytes, the simplest cells in the human body, it has been found that vitamin E acts as a protective agent for the cell membrane. Animal and human studies have shown that anemia is the first sign of vitamin E deficiency. When high doses of vitamin E are administered, hemolysis of the erythrocytes normalizes; see. William J. Darbey Vitamin Horm, 26 (50) pp. 685-704 (1968) and Phelps DL Pediatrics 63 (6) pp. 966-935 (1979). From these references it appears that when 200 to 800 mg of vitamin E is given orally for a period of 1 to 4 days, the hemolysis of the erythrocytes is significantly improved in comparison with patients with vitamin E deficiency.

Vitamin E has also been used to treat sickle cell anemia over a period of 6 to 35 weeks; see. Natt CL. At the. J. Clin. 33, pp. 968-971 (1980); Natt CL. At the. J. Clin. nutr. 32, pp. 1359-1362 (1979); Gawlik G.M. Fed. Proc. 35 (3), p. 252 (1976) and Gorash L. Bieri J.G. et al univ. Conn. Farmington, GT.

Furthermore, it is known that 750 mg of vitamin E was successfully used in a period of 3 to 6 months in thalassamy patients, a Nor malolysis of hemolysis of the erythrocytes was observed; see. Kahane I. ISR. J. med. 14 (1), pp. 11-15 (1976).

Vitamin E has continued to be used successfully in patients with acute hepatitis and alcoholic hepatitis who have a deficiency of vitamin E in the serum; see. Yoshiakawa T. Takemura S. Kato H. et al. Japan J. Gastrovent, 74/7, pp. 732-739 (1977). Finally, vitamin E was used in patients with iron deficiency anemia and brought about an improvement or normalization of lipid metabolism in the bone marrow over a period of 4 to 8 weeks; see. Takoshi Itaga, Central Clinical Laboratory Nagasaki University of Medicine, Japan.

It is also known that benzarone ointment and tablets are used to treat leg vein disorders and varicose veins and related disorders. A disadvantage of this active ingredient is that skin reactions, photosensitivity and allergies occur when exposed to light.

B. Helwig, Moderne Arzneimittel, 5th edition, pp. 1446 to 1447 (1980) states that the mechanism of action of vitamin E is only partially clarified. In particular, vitamin E then intervenes in the conversion and biosynthesis of carbohydrates, protein bodies, creatine and nucleic acids. The acceleration of tissue cleansing or detoxification by high doses of vitamin E was also observed. However, certain vitamin E concentrations and combinations of vitamin E with other active substances have not been investigated.

From W 083/01898 is a pharmaceutical active ingredient com known combination that contains vitamin A, vitamin E, almond oil, sesame oil and olive oil. The disadvantage of such a composition is that vitamin E is poorly absorbed by the skin. In addition, vitamin E certainly has no effect because it is only added in low concentrations.

It has surprisingly been found according to the invention that vitamin E combinations with vasodilators and / or blood circulation promoters are suitable for the treatment of venous diseases. Based on the current state of knowledge, this new area of indication was not foreseeable and opens up a new, broad field of application for vitamin E.

The present invention thus relates to agents for the treatment of diseases of the veins and the anal area, characterized in that they contain at least 200 mg of vitamin E per administration. Another object of the present invention are agents for the treatment of the veins and the anal area which vitamin E in combination with vasodilators and / or circulation-promoting agents. The present invention also relates to the use of vitamin E for the preparation of agents for the treatment of diseases of the anal region. Here, vitamin E can be combined with vasodilators and / or blood circulation-promoting agents, in particular those which have a circulation-promoting effect on the anal region or are among the coronary-effective vasodilators and / or blood circulation-promoting agents.

Venous disorders are understood to be varicose post-thrombotic syndrome. Typical indications are varicose veins with the signs of pain, nocturnal Leg cramps and swelling. Chronic venous insufficiency can also be alleviated faster according to the invention and brings significant long-term improvement in the long term.

It has surprisingly been found that the effect of vitamin E is increased considerably in the presence of vasodilators and / or circulation-promoting agents, and the treatment time is thereby shortened. The symptoms go away faster. The use of combination preparations containing vitamin E must, however, be carried out for a long time, approximately 6 months or longer.

Surprisingly, the penetration of vitamin E through the skin is particularly increased by the presence of circulation-promoting agents, such as heparin sodium, extr. Hippocastani etc., and consequently its effect is considerably increased. When using heparin sodium, the high dosage of 30,000 to 150,000 i.E. prefers. It has been found that the treatment time can be significantly reduced with these active ingredients in combination with a sufficient dose of vitamin E. The symptoms of the disease decrease more quickly, so that the dosage can be reduced after a while.

These results were unpredictable and enable therapy in which part of the chemical agent is replaced by a natural substance, which is also found in practically every cell in the body.

Agents that significantly increase the effect of vitamin E and can therefore be used for the invention are blood circulation-promoting agents such as extract Hippocastani, ß-hydroxyethyl rutoside, arnicae extract, nicotinic acid, nicotinic acid esters and derivatives, xantinol nicotinate and inositol nicotinate, as well as salicylic acid or its esters, dihydroergotoxin methane sulphonate, dihydroergocornine methane sulphonate sulphonate, dihydroergocornin methane sulphonate sulphonate Hydroxy ethyl salicylate. It has now been found that when these agents are used in combination with adequately dosed vitamin E, the symptoms in many patients decrease more quickly and the amount of these blood circulation-promoting agents can be reduced after several months.

The oral combinations between high-dose vitamin E and vasodilators or circulation-promoting agents are suitable for the treatment of diseases in the anal area. Here, even after taking them, there is rapid relief and elimination of the symptoms of hemorrhoidal diseases.

In addition to the aforementioned vasodilators or circulation-promoting agents, other similar products such as cinnarizine, vincamine, etc. can also be used.

Combinations according to the invention with sufficient amounts of vitamin E also improve blood flow to the extremities, the periphery of the eye, the inner ear and the cerebrum. The effectiveness of vitamin E in these indications is particularly surprising and opens up new areas of application for this vitamin.

Above all, sufficient is decisive for the effectiveness of vitamin E in combination with vasodilators and / or blood circulation enhancing agents Dosage that should be at least 80 mg. Lower doses of vitamin E are useless since large parts are destroyed by the stomach acid and thereby lose their effectiveness; see. Arthur Vogelsang in Angiology 21, pp. 275-279 (1970).

If in the past small amounts of vitamin E, namely up to 40 mg, were used in combination products, they were certainly completely ineffective due to the low dosage. For the treatment of venous diseases, the dosage should be in the range of 200 to 600 mg. Dosage forms containing 300 to 500 mg are preferably used. Typical combination preparations contain 300 to 400 mg of vitamin E. Experience has shown that, particularly in the case of combinations with nicotinic acid and its derivatives, high doses of vitamin E, between 300 and 500 mg per dosage form, are required.

Both the ester of natural or synthetic origin and the free tocopherol can be used as vitamin E in the oral dosage form.

In addition to active ingredients and vitamin E, the agents according to the invention contain conventional carriers and auxiliary substances. Since vitamin E is liquid at normal temperatures, the soft gelatin capsule is particularly suitable for this purpose. The active ingredients are introduced in vitamin E and, if desired, in a low-viscosity neutral oil and a solubilizer in a manner known per se in soft gelatin capsules; here too, suitable emulsifiers, such as Tween, can be used. The standard recipes from Scherer, Eberbach can be used here in particular. The use of these combinations in The form of drops, for example as an alcoholic solution, can also be suitable.

As conventional ointment or cream bases, Eucerin cum aqua, Ungt. Cordes, Ungt. Emulsificans, as well as other non-water-soluble ointment bases or mixtures thereof. Suitable ointment bases are, for example, wool wax, Vaseline DAB 8, thin paraffin and mixtures thereof. They can also contain emulsifiers such as cetylstearyl alcohol etc.

Unguentum alkoholum lanae aquosum with approx. 5 to 10% cetiol (oleic acid oleyl ester) and unguentum lanette, 24 T cetylstearyl alcohol, 16 T cetiol DAB 8, 60 T aqua conservata are also suitable as ointment bases.

With this combination, vitamin E is immediately absorbed into the skin. Of course, other vitamins, e.g. Vitamin B₁, B₂ and B₆ and tolerable pain relievers and local anesthetics are added. Local anesthetics are vasodilators. They can be added to the ointments as a surface anesthetic, such as anesthetic (Ethaforum) and tetracaine (Pantocaine), or in the capsules, such as procaine or procaine hydrochloride, etc.

The present invention accordingly describes liniments, for example cream, gel and ointment or lotion containing vitamin E, which in particular contain the following constituents:
80 to 30 wt .-% water, preferably
70 to 30% by weight of water, preferably 60 to 40% by weight
30 to 5% by weight of cetiol (oleyl oleate), preferably
25 to 7% by weight
30 to 2% by weight of cetyl stearyl alcohol or other aliphatic alcohols, preferably 25 to 2% by weight.

Instead of cetyl stearyl alcohol, other or some other emulsifying alcohols, e.g. aliphatic alcohols or wool wax alcohol or diols, stearinol, monoglycerides esterified with aliphatic acids or use similar substances. You can e.g. also add paraffin or petroleum jelly to make the ointment spreadable. Cetiol (oleyl oleate) can also be replaced by other emulsifiers, e.g. Tween 20 or Tween 80 etc., to be replaced in whole or in part.

The combination provides a particularly good combination as the basis for vitamin E-containing ointments or creams
30 to 20% by weight of cetyl stearyl alcohol,
20 to 10% by weight of cetiol (oleyl oleate),
60 to 40% by weight water (aqua conservata)
represents.

The ointment containing vitamin E is immediately absorbed into the skin.

It is known that water-containing ointment bases such as Unguentum emulsificans aquosum and Unguentum alkonolum lanae aquosum are suitable for processing water-soluble active ingredients. Here it is surprising that water-containing ointment bases, which are almost over 50% water-containing, are very well suited for processing fat-soluble active ingredients such as vitamin E. Examples of skin irritants or blood circulation agents are:
Ol. Juniperi
Ol.Pini Pumilionis (mountain pine oil)
Ol. Eucalypti
Ol. Rosmarinae
Tinct. Camphorae or camphor
usable.

As a vasodilating plant agent e.g. Extract. Call Calendulae from Blume and Herba calendulae. It has been found that these vasodilators or blood circulation agents significantly increase the effect of vitamin E or shorten the duration of treatment and eliminate the pain in the long term. Other derivatives of the blood circulation or vasodilators, e.g. Trimethylolrutoside can be used.

Surprisingly, it has also been found that high-dose vitamin E with blood circulation-promoting agents or derivatives as vein agents has particular advantages when vitamin A is added. In particular, the duration of treatment is shortened. This invention therefore further describes venous agents containing vitamins A and E and blood circulation-promoting agents.

Vitamins A and E tend to form lumps particularly in the presence of other active ingredients in the aqueous medium. There is therefore a risk that the fat-soluble valuable substances will not be absorbed.

It was surprisingly found that small amounts of emulsifier, about 1%, are sufficient to prevent the formation of lumps. The active ingredients are more easily dispersed or suspended in the aqueous medium. This has the intent partly that the absorption by the intestine is facilitated. A larger amount of emulsifier is not necessary, since 1 to 5% is usually sufficient to prevent the formation of lumps. You can also use emulsifiers up to 10% or more. The disadvantage, however, is that side effects may appear when large amounts are added and the medication is taken over long periods. The usual emulsifiers used in the medical preparations, such as Tween 20, Chremophore ^R , aliphatic alcohols etc. can be used. However, Tween 80 and Cetiol are preferred for this invention.

Lecithin can also be used as an emulsifier in a concentration between 1 and 13%. The absorption of the combination A + E, in particular of A, is thus favored. Small amounts of the lecithin emulsifier are sufficient to prevent clumping of the fat-soluble vitamins and to promote optimal absorption. The use of large amounts of lecithin, up to 50%, also has a positive effect. However, it is recommended to add approx. 1% conventional emulsifiers such as Tween 80. This promotes the miscibility of lecithin with the two vitamins and prevents clumping.

With regard to resoption, the use of conventional emulsifiers such as e.g. approx. 1% Tween 80 together with 1 to 13% lecithin. Instead of Tween 80, Teewn 20, cetiol, oleic acid oleyl ester and cremophore can also be used as emulsifiers. Soy lecithin is preferably used as the lecithin preparation.

Vitamin A can function as vitamin A palmitate, as well as vita min-A acetate, as well as other esters of vitamin A, and ß-carotene can be used.

Vitamin E can be used in all of its alpha forms, both as free and as an ester. This ester can be used as acetate, succinate or as another ester. You can also prepare other dosage forms, such as tablets or dragées, if you use vitamin E in solid form. It can also be used as an alcoholic solution. The amount of vitamin E should be dosed as high as possible, between 200 to 600 mg, preferably between 300 to 500 mg per dosage form. Vitamin A should be selected so that the maximum daily dose does not exceed 50,000 IU, ie if two dosage forms are used per day, the dosage should be a maximum of 25,000 IU per dosage form. Other additives such as vitamins, for example B-series vitamins or analgesics, etc. can also be added. The following substances or their derivatives can be used as circulation-promoting agents: Buflomedil Inositol nicotinate Nicotinic acid Cinnarizine Bencyclan hydrogen fumarate Vincamin Dihydroergotoxin methanesulphonate Pentoxifylline β-pyridylcarbinol Bamethane sulfate Ginkoflavone glycosides β-hydroxyethyl rutoside Extract Hippocastani Flunarizine or the dihydrochloride

These substances can be combined with vitamins A and E and can also be used against arteriosclerosis. The circulation-promoting agents can also be used in the form of a sustained release.

It has surprisingly been found that the combination of benzarone with vitamin E or vitamin A + E eliminates the disadvantageous effects which occur when using the benzarone ointments and tablets known to date. It also significantly increases and intensifies the effects of benzarone on the veins. The treatment time is significantly reduced compared to the treatment with benzarone without the addition of vitamins A and E according to the invention.

Vitmin E must be present in the capsules in a sufficiently high dosage, between 200 and 600 mg, preferably between 300 and 500 mg, per capsule. 400 to 500 mg are particularly preferred.

Vitamin E between 5 and 15% by weight, preferably between 7 and 10% by weight, is used in the production of ointments and creams. Typical examples are between 3 and 10% by weight. The benzarone content is up to 12% by weight, preferably 3 to 9% by weight.

The usual well-known ointments, cream and milk bases such as Ungt. cordes, Eucerin cum aqua, polyethylene glycol ointment bases, stearinol, monoglycerides esterified with aliphatic acids and triglycerides or their mixtures with aliphatic alcohols or their derivatives, such as emulsifying cetyl stearyl alcohol, and wool wax alcohol or diol, can be used.

Paraffin or petroleum jelly or other suitable substances can also be added to make the ointment spreadable do. Cetiol (oleyl oleate) can also be replaced in whole or in part by other emulsifiers, for example Tween 20 or 80 etc.

However, it has been found that the best combination as the basis for vitamin E-containing ointments or creams is as follows:
30 to 20% by weight of cetyl stearyl alcohol
20 to 10% by weight of cetiol (oleyl oleate)
60 to 40% by weight water (aqua conservata)

This vitamin E-containing ointment is immediately absorbed into the skin.

Other useful known additives, such as vitamin A, one or more vitamins of the B series, and cod liver oil, also unsaturated fatty acids, such as e.g. Linoleic acid, octadeca-9,11-dienoic acid or silicone oil or polysiloxic acid can be added to the vitamin E liniments to achieve better properties. It was also found that vitamin E in combination with phosphorus lipids, which consists of choline phosphoric acid diglyceride esters with predominantly unsaturated fatty acids, especially linoleic acid, linolenic and oleic acid, has excellent properties for protecting the skin. According to the invention, vitamin E is preferably in its free form, e.g. D-alpha-tocopherol concentrate and DL-alpha-tocopherol used.

You can also use rubbing in alcoholic solutions, e.g. Carry out isopropyl alcohol or other alcohols.

Proof of this invention is the proof that Vi tamin E, especially in its free forms, for example DL-alpha-tocopherol and / or D-alpha-tocopherol, is transdermal. Vitamin A can be added in the form of acetate or palmitate or any other suitable form, for example β-carotene. Benzarone or its derivatives or mixtures can be used.

It has now been found that, surprisingly, vitamin E is also outstandingly suitable for the treatment of diseases of the anal region. In particular, it is suitable for the treatment of hemorrhoids, varices, age-related venous weakness, capillarophathy, thrombophlebitis in the anal area, pruritus ani, anal fissures, anal rhagades and wet anal eczema.

Based on the current state of knowledge, this new area of indication was not foreseeable and opens up a new and broad range of applications for vitamin E.

In principle, it is possible to administer vitamin E orally for these indications, so that all previously known oral forms of administration can be used. Soft gelatin capsules are particularly suitable which contain either alpha tocopherol from soybean, corn or wheat seedlings, or else D, L-alpha tocopherol acetate.

Suppositories and ointments are particularly suitable for the new use of vitamin E for the treatment of diseases of the anal area.

These new forms of application of vitamin E are particularly preferred for two reasons: With their help it is possible to get vitamin E into the desired range without delay and in relatively high concentrations to provide. Furthermore, the loss of vitamin E in the case of oral administration is avoided since it is known that vitamin E is destroyed to a considerable extent by gastric acid.

The present invention thus relates to the use of vitamin E for the treatment of diseases of the anal region. The invention further relates to the use of vitamin E for the production of suppositories and ointments for the treatment of these diseases.

The suppositories should preferably contain 200 to 600 mg of vitamin E and conventional carriers and auxiliaries. Amounts of 300 to 500 mg of vitamin E are particularly preferred. If desired, vasodilators and / or circulation-promoting agents are additionally used. These agents include, in particular, heparin sodium, extract. Hippocastani, extract. or tinct. arnicae, ß-hydroxyethyl-rutoside, salicylic acid esters, nicotinic acid esters, especially the nicotinic acid benzyl ester. These additional active ingredients are used in amounts of 2 to 500 mg per suppository. They increase and accelerate the action of vitamin E. Other active substances that come into question are those that are already known for the treatment of diseases of the anal area. These include zinc oxide, bismuth gallate, allantoin, dexapanthenol, hydrocortinson acetate, prednisolone acetate and benzocaine.

Zinc oxide and Peru balsam as well as soft gelatin capsules in suppository form are suitable as usual carriers and auxiliaries for suppositories according to the invention. Stadimol (Stada or Olium) (cocoa) is preferably used as the suppository base. Possibly. the usual emulsifiers can also be added.

The ointments according to the invention contain vitamin E and are produced on the basis of conventional ointment bases. If desired, they too can contain other customary and known active substances for the treatment of diseases of the anal region.

If desired, vasodilators and / or circulation-promoting agents are additionally used. These agents include, in particular, heparin sodium, extract. Hippocastani, extract, or tinct. arnicae, ß-hydroxyethyl-rutoside, salicylic acid esters, nicotinic acid esters, especially the nicotinic acid benzyl ester and flunarizine dihydrochloride.

As usual ointment or cream bases Eucerin cum aqua, Ungt. Cordes Ungt. emulsificans, as well as other non-water-soluble ointment bases or mixtures thereof. Suitable ointment bases are, for example, wool wax, Vaseline DAB 8, thin paraffin and mixtures thereof. They can also contain emulsifiers such as cetylstearyl alcohol etc.

The present invention thus also relates to the new application forms, namely suppositories and ointments containing vitamin E and customary auxiliaries and carriers.

To treat the disease of the anal area, vitamin E is initially used several times a day later only once a day.

In the case of oral use, the dosage should be at least 200 to 400 mg of vitamin E, since it is known that part of the vitamin E is destroyed again by gastric acid. When using suppositories, the Amount of vitamin E 200 to 500 mg vitamin E per application. Ointments should contain 5 to 15% by weight of vitamin E. Both natural D-alpha-tocopherol and its concentrates or synthetic D, L-alpha-tocopherol can be considered as vitamin E. The acetates customarily used for oral preparations are out of the question for ointments and suppositories, since the acetates are ineffective in the unsplit form and are not split into the free vitamin E during absorption in the anal region.

When treating or stimulating the sexual areas and organs, the vitamin E suppositories could also be used to improve and eliminate the symptoms. However, the appropriate additives for the supportive treatment had to be selected in the areas of application or in the various applications. The usual auxiliaries and carriers can be used in the manufacture of suppositories. Soft gelatin rectal capsules and emulsifiers can also be used. However, suppositories containing high-dose vitamin E alone can be used to treat the above diseases or to stimulate the sexual areas.

The combinations with blood circulation-promoting agents such as extract Hippocastani or ß-hydroxyethylrutoside or also rutoside derivatives which contain several hydroxyethyl groups can be used. Nicotinic acid or its esters or derivatives, such as, for example, benzyl nicotinate or β-hydroxyethyl nicotinate, etc., can bring advantages and increase the effect of vitamin E and shorten the healing process. Other useful substances such as Extract muirae can be used to treat or stimulate the sexual organs puamae, Extract testes bovis, e.g. aqueous extracts from these substances or similar products.

Such vitamin E suppositories can also be used to treat various known prostate diseases such as Inflammation or congestion etc. can be used for induction treatment. An amount between 200 to 500 mg vitamin E per suppository is preferred for induction treatment for infertility, for stimulating the sexual organs. Typical examples contain 300 to 450 mg of vitamin E.

The advantage of using suppositories is that vitamin E is fully used or used and is not destroyed by stomach acid.

In the following examples vein remedies are explained:

example 1

100 g of ointment contain:
400 mg allantoin;
400 mg dexapanthenol;
5000 mg D-alpha tocopherol;
30,000 IU heparin sodium;

Example 2

100 g of ointment contain:
2.5 g of O- (β-hydroxyethyl) rutoside;
7.5 g D-alpha tocopherol or D, L-alpha tocopherol;

Example 3

100 g of ointment contain:
400 mg allantoin;
400 mg dexapanthenol;
8.8 g D-alpha-tocopherol or D, L-alpha-tocopherol;
30000 IU heparin sodium

Example 4

100 g of ointment contain:
4.5 g extract Hippocastani (contains approx. 800 mg aescin);
8.0 g D-alpha tocopherol;

Example 5

100 g of gel contain:
50,000 IU heparin sodium;
12 g Arnica flower extract ((1:10) alcohol 60%);
25 g tinct. Hippocastani e sem. Corresponds to 1: 1
0.65 aescin;
7.5 g D-alpha tocopherol;

Example 6

100 g of gel contain:
7.0 g of β-hydroxyethyl salicylate;
7.0 g D-alpha tocopherol;

Example 7

Rheumatic plaster 15 x 25 cm contains or is prepared on one side with:
70 mg Extract Arnicae;
70 mg Extract Capsici;
30 mg extract Bella donae;
1500 mg D-alpha tocopherol concentrate;

Example 8

100 g of ointment contain:
10 g benzocaine (anesthetic);
8 g D-alph tocopherol concentrate;
1 g benzyl nicotinate;

Example 9

100 g of ointment contain:
3 g of hydroxyethyl salicylate;
1 g benzyl nicotinate;
7 g D-alpha tocopherol;

Example 10

100 g of ointment contain:
8 g D-alpha tocopherol;
400 mg allantoin;
400 mg dexapanthenol;
150000 IU heparin sodium;

Example 11

Capsules contain:
250 mg nicotinic acid;
400 mg D, L-alpha-tocopherol acetate;
150 mg soybean oil;

Example 12

Capsules contain:
200 mg of β-hydroxyethyl rutoside;
400 mg D-alpha tocopherol acetate;
180 mg soybean oil;

Example 13

Capsules contain:
150 mg extract Hippocastani (contain 25 mg aescin);
400 mg D-alpha tocopherol;
150 mg soybean oil;

Example 14

Capsules contain:
300 mg xantinol nicotinate;
400 mg D-alpha tocopherol;
190 mg soybean oil;

Example 15

Capsules contain:
150 mg extract Hippocastani (contain 25 mg aescin);
350 mg vitamin E;
150 mg soybean oil;

Example 16

Capsules contain:
5 mg vitamin B₁;
5 mg vitamin B₂;
5 mg vitamin B₆;
200 mg of β-hydroxyethyl rutoside;
300 mg vitamin E;
50 mg nicotinic acid amide;
200 mg soybean oil;

Example 17

Capsules contain:
100 mg nicotinic acid;
100 mg horse chestnut extract (contain 16 mg aescin);
300 mg D-alpha tocopherol acetate;
200 mg soybean oil;

Example 18

Capsules contain:
200 mg inositol nicotinate;
400 mg D-alpha tocopherol concentrate;
150 mg soybean oil;

Example 19

Capsules contain:
50 mg procaine hydrochloride;
400 mg D-alpha tocopherol concentrate;
150 mg soybean oil;

Example 20

50 mg procaine hydrochloride;
400 mg D, L-alpha-tocopherol acetate;
5 mg vitamin B₁;
5 mg vitamin B₂;
5 mg vitamin B₆;
150 mg soybean oil or corn oil

Example 21

drops
100 ml of 90% ethyl alcohol contains:
40 g D, L-alpha-tocopherol acetate:
4.5 g extract Hippocastani (contain 750 mg aescin);

Example 22

Capsules contain:
4.5 mg dihydroergotoxin methane sulphonate;
400 mg D, L-alpha-tocopherol acetate;

Example 23

Capsules contain:
50 mg procaine hydrochloride;
200 mg nicotinic acid;
300 mg vitamin E;
150 mg corn oil.

Example 24

Capsules contain:
150 mg bencyclan hydrogen fumarate;
300 mg vitamin E as D, L-alpha tocopherol acetate;
150 mg soybean oil.

Example 25

Contains an ointment
10 g D-alpha tocopherol
50,000 IU heparin sodium
ad 100 ointment base
22 parts of cetyl stearyl alcohol
18 T cetiol
60 T water

Example 26

7 g vitamin E (D-alpha-tocopherol)
1 g of benzyl nicotinate
1 g camphor
ad 100 ointment base
17 T cetyl stearyl alcohol
8 T White Vaseline
15 T cetiol
60 T water (aqua conservata)

Example 27

7 g vitamin E.
15 g tinct. calendualae
ad 100 ointment base
13 t of wool wax alcohol
2T cetyl stearyl alcohol
20 T cetiol
5 T paraffin
50 T water (aqua conservata)

Example 28

8 g vitamin E (DL-alpha-tocopherol)
1.5 g rosemary oil
1 g extract Hippocastani (standardized to at least 8% aescin)
1 g oil juniperi
ad 100 ointment base as example 25

Example 29

Solution
8 g vitamin E (D-alpha-tocopherol concentrate)
1 g mountain pine oil (oil pini pumilionis)
1 g eucalyptus oil
1 g oil juniperi
ad 100 isopropyl alcohol

Example 30

7 g D-alpha tocopherol concentrate
2 g tinct. arnicae
2 g of salicyl-ß-hydroxyethyl ester
ad 100 ointment base as example 25

Example 31

Solution according to example 29
7.0 g of vitamin E.
1.0 g mountain pine oil
1.0 g Arnica tincture
ad 100 isopropyl alcohol

Example 32

Beispiel 42 Kapseln enthaltend Nicotinsäure 300 mg Vitamin E 400 mg Vitamin A Palmitat 50.000 I.E. Cetiol (Oleylsäureester) 20 mg Sojaöl 150 mg Beispiel 43 Kapseln enthaltend DL-alpha-Tocopherolacetat 400 mg β-Hydroxyäthylrutosid 300 mg Vitamin A Palmitat 25.000 I.E. Sojaöl 120 mg Beispiel 44 Kapseln enthaltend Pentoxifyllin 400 mg Vitamin E DL-alpha-Tocopherolacetat 400 mg Vitamin A Palmitat 50.000 I.E. Tween 80 10 mg Sojaöl 150 mg Beispiel 45 Kapseln enthaltend Bamethansulfat 25 mg DL-alpha-Tocopherolacetat 350 mg Vitamin A Palmitat 25.000 I.E. Sojaöl 150 mg Beispiel 46 Kapseln enthaltend Vincamin 30 mg Vitamin E DL-alpha-Tocopherolacetat 400 mg Vitamin A Palmitat 30.000 I.E. Sojaöl 150 mg 9.0 g of vitamin E.
20.0 g tinct. Calendulae
ad 100 ointment base like 25 Example 33 Containing capsules Pentoxifylline 400 mg Vitamin E. 400 mg Vitamin A acetate 25,000 IU Soybean oil 120 mg Example 34 Containing capsules Naftidirofuryl hydrogen oxalate 100 mg Vitamin E. 500 mg Vitamin A palmitate 30,000 IU Soybean oil 150 mg Example 35 Containing capsules Cinnarizine 75 mg Vitamin E. 400 mg Vitamin A palmitate 25,000 IU Vitamin B₁, B₂, B₆ in equal parts 10 mg Vitamin B12 5 µg Soybean oil 150 mg Example 36 Contain 100 ml drops of ethyl alcohol Cinnarizine 7.5 g Vitamin E. 4.0 g Vitamin A palmitate 2.5 million units Example 37 Containing capsules Xantinol nicotinate 500 mg Vitamin E (dl-alpha-tocopherol) 400 mg Vitamin A palmitate 25,000 IU Tween 80 20 mg Soybean oil 150 mg Example 38 Drop in 100 ml of ethyl alcohol Dihydroergotoxin methanesulphonate 1.5 g from (0.5 g dihydroergocristine methanesulphonate 0.5 g dihydroergocornine methanesulfonate 0.333 g alpha-dihydroergocryptine methanesulfonate 0.167 g β-dihydroergocryptin methanesulphonate) Vitamin E (DL-alpha-tocopherol acetate) 3.5 g Vitamin A palmitate 2.5 million units Example 39 Containing capsules β-pyridyl carbinol tartrate 360 mg corresponds to 150 mg pyridylcarbinol D-alpha tocopherol acetate 400 mg Vitamin A palmitate 50,000 IU Soybean oil 150 mg Example 40 Containing capsules DL-alpha tocopherol 400 mg β-hydroxyethyl rutoside 300 mg Vitamin A palmitate 30,000 IU Soybean oil 150 mg

Example 42 Containing capsules Nicotinic acid 300 mg Vitamin E. 400 mg Vitamin A palmitate 50,000 IU Cetiol (oleic acid ester) 20 mg Soybean oil 150 mg Example 43 Containing capsules DL-alpha tocopherol acetate 400 mg β-hydroxyethyl rutoside 300 mg Vitamin A palmitate 25,000 IU Soybean oil 120 mg Example 44 Containing capsules Pentoxifylline 400 mg Vitamin E DL-alpha tocopherol acetate 400 mg Vitamin A palmitate 50,000 IU Tween 80 10 mg Soybean oil 150 mg Example 45 Containing capsules Bamethane sulfate 25 mg DL-alpha tocopherol acetate 350 mg Vitamin A palmitate 25,000 IU Soybean oil 150 mg Example 46 Containing capsules Vincamin 30 mg Vitamin E DL-alpha tocopherol acetate 400 mg Vitamin A palmitate 30,000 IU Soybean oil 150 mg

The following examples relate to strengthened venous agents containing benzarone and vitamin E.

Example 47

200 mg benzarone
400 mg DL-alpha tocopherol acetate
120 mg soybean oil

Example 48

100 mg benzarone
500 mg D-alpha tocopherol concentrate
80 mg soy

Example 49

According to example 47.
Instead of 400 mg DL-alpha-tocopherol acetate, 300 mg was used.

Example 50

9 g D-alpha tocopherol concentrate
2 g benzarone
ad 100.0 from an ointment base consisting of 20% by weight cetylstearyl alcohol, 20% by weight cetiol and 60% by weight aqua conservata.

Example 51

10 g DL-alpha tocopherol acetate
2 g benzarone
ad 100 from an ointment base such as under 50, but instead of 60% by weight of water only 55% by weight and 5% by weight of Vaseline album.

Example 52

25,000 IU of vitamin A palmitate
400 mg dl-alpha tocopherol acetate
200 mg benzarone
100 mg soy

The following are examples of venous agents and suppositories used to treat the sexual area:

Example 53

Suppositories included
250 mg D-alpha tocopherol concentrate
30 mg of benzyl nicotinate
100 mg of dried, de-proteinated, aqueous extract from testis bovis
70 mg extract muirae puamae sicc.
ad 2.0 g Stadimol

Example 54

Suppositories included
450 mg dl-alpha tocopherol
40 mg cetiol (oleic acid oleyl ester)
150 mg zinc oxide
ad 2.0 g Stadimol

Example 55

Suppositories included
400 mg vitamin E.
200 mg of β-hydroxyethylrutoside
40 mg cetiol
ad 2.0 g Stadimol

Example 56

Suppositories included
250 mg vitamin E.
250 mg extract Hippocastani (contains approx. 80 mg aescin) ad 2.0 g stadimol

Example 57

Suppositories were produced according to Example 55, but with
300 mg of vitamin E and
200 mg tri-ethylolrutoside

The following examples describe the preparation of suppositories and ointments for the treatment of diseases of the anal region in some typical compositions. In principle, other recipes can also be used.

Example 58

D-Alpha-tocopherol concentrate and zinc oxide are mixed together in a weight ratio of 3: 1 and processed into suppositories. The suppositories each contain 450 mg D-alpha-tocopherol concentrate and 150 mg zinc oxide. This corresponds to a vitamin E content of approx. 1000 to 1050 IU / g.

Example 59-64

Suppositories containing vitamin E were produced according to the following recipes: 1) D-alpha-tocopherol concentrate (approx. 99%) 450 mg zinc oxide 150 mg Bismuth gallate 150 mg Allantoin 50 mg Dexapanthenol 50 mg 2) D-alpha tocopherol concentrate 300 mg zinc oxide 140 mg Bismuth gallate 140 mg Extr. Hippocastani 190 mg Extr. Hamamelidis 70 mg Dexapanthenol 10 mg Allantoin 30 mg 3) Heparin 210 IU 2 mg D-alpha tocopherol concentrate 450 mg Dexapanthenol 20 mg Allantoin 50 mg 4) Heparin 210 IU 2 mg D-alpha tocopherol concentrate 450 mg Dexapanthenol 20 mg Allantoin 50 mg Hydrocortisone acetate 5 mg 5) Heparin 210 IU 2 mg D-alpha tocopherol concentrate 400 mg Peru balsam 50 mg Benzocaine 50 mg 6) Heparin 210 iE 2 mg D-alpha tocopherol concentrate 400 mg Peru balsam 50 mg Benzocaine 50 mg Prednisolone acetate 5 mg

Example 65

Other suppository formulations contain 100 mg, 150 mg and 200 mg of D-alpha-tocopherol or D, L-alpha-tocopherol.

Example 66

Wool wax DAB 8 (30 wt .-%), Vaseline DAB 8 (20 wt .-%) and paraffin thin (50 wt .-%) are mixed together and with D-alpha-tocopherol or D, L-alpha-tocopherol mixed an ointment so that 7.5 g of vitamin E are contained in 100 g of ointment.

Further ointment formulations were prepared with 8.0% and 0% D, L-alpha-tocopherol, or 8% by weight D-alpha-tocopherol concentrate and 1% by weight of prednisolone and allantoin or 7% by weight. D-alpha-tocopherol concentrate or D, L-alpha-tocopherol with 6.5% by weight Ext. Sem. Hippocast. (Spir. Spiss 5: 1), 12.0% by weight basic Bismuth gallate and 0.15% by weight dexapanthenol.

Another ointment contained 10,000 IU. Heparin sodium and 8% by weight D-alpha-tocopherol.

A similar recipe contained 10,000 IU. Heparin sodium and 7.5% by weight D-alpha-tocopherol or D, L-alpha-tocopherol.

Further ointment formulations contained in 100 g 0.25 g horse chestnut extract (standardized to at least 8% aescin), witch hazel extract (alcoholic water extract) 1.5 g 12 g zinc oxide and 7.5 g D-alpha-tocopherol concentrate, or
2.0 g benzocaine, basic bismuth gallate, 8.0 g, 10.0 g Peru balsam and 8.0 g D-alpha-tocopherol or D, L-alpha-tocopherol, or
0.4 g allantoin, 0.4 g dexapanthenol, 9 g D-alpha-tocopherol and 30,000 iE heparin sodium, or
2.5 g of O- (β-hydroxyethyl) rutoside and 7.5 g of D-alpha-tocopherol concentrate or D, L-alpha-tocopherol, or
4.5 g extract. Hippocastani (containing approx. 800 mg aescin) and 8.0 g D-alpha-tocopherol concentrate, or
5,000 IU heparin sodium, 12 g arnica flower extract (1:10 alcohol 60%), 25 g tinct. Hippocastani e sem. 1: 1 corresponding to 0.65 aescin and 7.5 g D-alpha-tocopherol, or
7.0 g of β-hydroxyethyl salicylate and 7.0 g of D-alpha-tocopherol.

Example 68-74

• 1) contains anal ointment
  7.0 g of vitamin E.
  ad 100 ointment base
  22 g cetyl stearyl alcohol
  18 g cetiol
  60 g water
• 2) contains anal ointment
  210 IU heparin sodium
  8.0 g D-alpha tocopherol concentrate
  ad 100 ointment base as 1
• 3) 7.0 g of vitamin E DL-alpha-tocopherol
  6.0 g condensation products from metacresol (95% monosulfonic acid) and formaldehyde, average molecular weight 350 to 600)
  1.0 g benzocaine
  ad 100 ointment base
  17.0 g cetyl stearyl alcohol
  8.0 g of white petroleum jelly
  10.0 g paraffin
  15.0 g cetiol
  50.0 g of aqua conservata
• 4) suppositories
  120 mg of condensation products made from sulfonated metacresol (95% monosulfonic acids) and formaldehyde (average molecular weight 350 to 600)
  350 mg vitamin E dl-alpha tocopherol
  300 mg benzocaine
  30.0 mg cetiol
• 5) Suppositories included
  300 mg D-alpha tocopherol concentrate
  140 mg zinc oxide
  140 mg bismuth gallate
  190 mg extract. Hippocastani
  10 mg dexapanthenol
  30 mg allantoin
  50 mg cetiol
• 6) Contains ointment
  150 mg aqueous suspension the corpuscular components and metabolic products of Escherichia coli approx. 300 million
  3 mg phenol liquifactum
  80 mg vitamin E.
  ad 1.0 g ointment base as 3

Examples 75 to 90 relate to venous agents that contain vitamins A and E and lecithin. 1) Containing capsules Pentoxifylline 400 mg Vitamin E DL-alpha tocopherol acetate 400 mg Vitamin A acetate 25,000 IU Soy lecithin 200 mg Soybean oil 120 mg Tween 80 8 mg 2) Containing capsules Naftidirofuryl hydrogen oxalate 100 mg Vitamin E D-alpha tocopherol concentrate 500 mg Vitamin A palmitate 30,000 IU Soy lecithin 25 mg Soybean oil 150 mg 3) Containing capsules Cinnarizine 75 mg Vitamin E D-alpha tocopherol acetate 400 mg Vitamin A palmitate 25,000 IU Vitamin B₁, B₂, B₆ in equal parts 10 mg Vitamin B12 5 µg Soybean oil 100 mg Soy lecithin 280 mg 4) Contain 100 ml drops of ethyl alcohol Cinnarzin 7.5 g Vitamin E. 4.0 g Vitamin A palmitate 2.5 million units Lecithin 2.5 g 5) Containing capsules Xantionolnicotinate 500 mg Vitamin E (DL-alpha-tocopherol) 400 mg Vitamin A palmitate 25,000 IU Tween 80 20 mg Soybean oil 150 mg Soy lecithin 25 mg 6) Drop in 100 ml of ethyl alcohol Dihydroergotoxin methanesulphonate 1.5 g out (0.5 g dihydroergocristine methanesulphonate 0.5 g dihydroergocornine methanesulfonate 0.333 mg alpha-dihydroergocryptin methanesulphonate 0.167 mg β-dihydroergocryptin methanesulphonate) Vitamin E (DL-alpha-tocopherol acetate) 3.5 g Vitamin A palmitate 2.5 million units Soy lecithin 3.5 g 7) Containing capsules β-pyridyl carbinol tartrate 360 mg corresponds to 150 mg pyridylcarbinol D-alpha tocopherol acetate 400 mg Vitamin A palmitate 50,000 IU Soybean oil 100 mg Soy lecithin 150 mg Tween 20 6 mg 8) Containing capsules DL-alpha tocopherol 400 mg β-hydroxyethyl rutoside 300 mg Vitamin A palmitate 30,000 IU Soybean oil 100 mg Soy lecithin 250 mg 9) Containing capsules Ginkoflavone glycosides 3.0 mg Vitamin E DL-alpha tocopherol acetate 300 mg Vitamin A palmitate 25,000 IU Soybean oil 100 mg Soy lecithin 200 mg 10) Nicotinic acid 300 mg Vitamin E. 400 mg Vitamin A palmitate 50,000 IU Cetiol (oleic acid ester) 10 mg Soybean oil 100 mg Soy lecithin 20 mg 11) Containing rectal capsules DL-alpha-tocopherol USP, 1,100 IU vit.E / g 472.5 mg Zinc Oxide Ph.Eur.I, USP 150.0 mg Rape oil DAC 467.50 mg Triglycerides, saturated, C 8 - C 18 500.0 mg Soy lecithin 120.0 mg Oleic acid oleate ester DAB (= cetiol) 30.0 mg 12) Containing rectal capsules DL-alpha-tocopherol USP, 1,100 IU vita. E / g 420.0 mg Troxerutin (= trihydroxyethylrutin) 100.0 mg Rape oil DAC 475.0 mg Triglycerides, saturated 500.0 mg Soy lecithin 120.0 mg Oleic acid oleate ester DAB (= cetiol) 25.0 mg 13) Containing capsule DL-alpha tocopherol 200 mg Lecithin 500 mg Soy 180 mg Tween 80 10 mg 14) capsule according to 13) but additionally containing 1500 IU vitamin A palmitate.
15) Capsule according to 13) and 14) but containing D, L-alpha-tocopherol instead of D-alpha-tocopherol. 16) Containing capsule DL-alpha tocopherol 400 mg Lecithin 400 mg Soy 200 mg Tween 80 15 mg 17) capsule according to 16) but additionally containing 15,000 IU of vitamin A palmitate or vitamin A acetate or 9.5 mg of β-carotene.

By using the products containing lecithin, the cholesterol level is lowered.

Claims (10)

1. Means for the treatment of diseases of the veins and to improve the blood flow to the extremities, the periphery of the eye, the inner ear and the cerebrum by oral administration of the active compounds, characterized by a content of vitamin E in the range from 200 to 600 mg per Dosage unit, one or more vasodilators and / or blood circulation enhancers as well as, where appropriate, other active ingredients and conventional carriers and auxiliaries. 2. Composition according to claim 1, characterized by a content of vitamin E in the range from 300 to 500 mg, preferably from 400 to 500 mg per administration unit. 3. Composition according to one of claims 1 or 2 in the form of capsules. 4. Composition according to one of claims 1 to 3, characterized in that it is cinnarizine, bencyclan hydrogen fumarate, dihydroergotoxin methanesulfonate, pentoxifylline, ß-pyridylcarbinol, ß-hydroxyethylruthoside, bamethanesulfate, ginkgoflavone glycoside, bifluoromethanolic acid, flufhydrochloride or its extract, flufunyl chloride, extractum hippomidyl chloride, extract hippomethane chloride, Extractum hippomidyl chloride , Inositol nicotinate or more of the compounds mentioned. 5. Compositions according to claim 4, characterized in that they contain bencyclan hydrogen fumarate or pentoxifylline as circulation-promoting agents. 6. Composition according to one of claims 1 to 5, characterized in that they additionally contain one or more anticoagulant (s) or vitamin A and / or one or more emulsifiers and / or lecithin. 7. Composition according to one of claims 1 to 5, characterized in that they additionally contain benzarone and / or its derivatives and vitamin A. 8. Composition according to one of claims 1 to 7, characterized in that they are used as emulsifiers Tween R 80 and / or oleic acid oleyl ester in amounts of 0.1 to 13%, preferably in amounts of 1 to 10%, particularly preferably in amounts of 1 up to 5%. 9. Composition according to one of claims 1 to 8, characterized in that they additionally contain lecithin in amounts of 0.4 to 50%, preferably in amounts of 1 to 13% and optionally in addition to lecithin 0.4 to 5% of an emulsifier . 10. Composition according to one of claims 1 to 9, characterized in that it contains vitamin E of natural or synthetic origin in the form of D-α-tocopherol, DL-α-tocopherol and / or their esters, preferably their acetates and / or succinates, contain.